Methods of treatment using single doses of oritavancin

ABSTRACT

Glycopeptide antibiotics, such as oritavancin, demonstrate significant activity against a wide range of bacteria. Methods for the treatment, prophylaxis and prevention of bacterial infection and disease in animals, including humans, using a single dose of oritavancin over the course of therapy, are described.

BACKGROUND OF THE INVENTION

Oritavancin diphosphate (oritavancin) is a semi-syntheticlipoglycopeptide derivative of a naturally occurring glycopeptide. Itsstructure confers potent antibacterial activity against gram-positivebacteria, including vancomycin-resistant enterococci (VRE), methicillin-and vancomycin-resistant staphylococci, and penicillin-resistantstreptococci. The rapidity of its bactericidal activity againstexponentially-growing S. aureus (≧3-log reduction within 15 minutes to 2hours against MSSA, MRSA, and VRSA) is one of the features thatdistinguishes it from the prototypic glycopeptide vancomycin (McKay etal., J Antimicrob Chemother. 63(6):1191-9 (2009), Epub 2009 Apr. 15).

Oritavancin inhibits the synthesis of peptidoglycan, the majorstructural component of the bacterial cell wall by a mechanism that isshared with glycopeptides, such as vancomycin (Allen et al., AntimicrobAgents Chemother 41(1):66-71 (1997); Cegelski et al., J Mol Biol357:1253-1262 (2006); Arhin et al., Poster C1-1471: Mechanisms of actionof oritavancin in Staphylococcus aureus [poster]. 47th Intersci ConfAntimicro Agents Chemo, Sep. 17-20, 2007; Chicago, Ill.). Oritavancin,like vancomycin, binds to the Acyl-D-Alanyl-D-Alanine terminus of thepeptidoglycan precursor, lipid-boundN-acetyl-glucosamine-N-acetyl-muramic acid-pentapeptide (Reynolds, Eur JClin Microbiol Infect Dis 8(11):943-950 (1989); Nicas and Allen,Resistance and mechanism of action. In: Nagarajan R, editor.Glycopeptide antibiotics. New York: Marcel Dekker 195-215 (1994); Allenet al., Antimicrob Agents Chemother 40(10):2356-2362 (1996); Allen andNicas, FEMS Microbiology Reviews 26:511-532 (2003); Kim et al.,Biochemistry 45:5235-5250 (2006)). However, oritavancin inhibits cellwall biosynthesis even when the substrate is the altered peptidoglycanprecursor that is present in VRE and vancomycin-resistant S. aureus(VRSA). Thus, the spectrum of oritavancin antibacterial activity extendsbeyond that of vancomycin to include glycopeptide-resistant enterococciand staphylococci (Ward et al., Expert Opin Investig Drugs 15:417-429(2006); Scheinfeld, J Drugs Dermatol 6:97-103 (2007)). Oritavancin mayinhibit resistant bacteria by interacting directly with bacterialproteins in the transglycosylation step of cell wall biosynthesis(Goldman and Gange, Curr Med Chem 7(8):801-820 (2000); Halliday et al.,Biochem Pharmacol 71(7):957-967 (2006); Wang et al., Poster C1-1474:Probing the mechanism of inhibition of bacterial peptidoglycanglycotransferases by glycopeptide analogs. 47th Intersci Conf AntimicroAgents Chemo, Sep. 17-20, 2007). Oritavancin also collapsestransmembrane potential in gram positive bacteria, leading to rapidkilling (McKay et al., Poster C1-682: Oritavancin disrupts transmembranepotential and membrane integrity concomitantly with cell killing inStaphylococcus aureus and vancomycin-resistant Enterococci. 46thIntersci Conf Antimicro Agents Chemo, San Francisco, Calif., Sep. 27-30,2006). These multiple effects contribute to the rapid bactericidalactivity of oritavancin.

Oritavancin is in clinical development against serious gram-positiveinfections, where administration of the drug is via intravenous infusionusing several dosages administered over a series of days. Thedevelopment of alternative dosing regimens for the drug could expandtreatment options available to physicians. The present invention isdirected to novel dosing regimens.

BRIEF SUMMARY OF THE INVENTION

As disclosed herein, it has been discovered that the glycopeptideantibiotic oritavancin, also known asN^(DISACC)-(4-(4-chlorophenyl)benzyl)A82846B and LY333328, demonstratesclinically significant therapeutic activity against bacterial infectionswhen administered to a subject in one dose over a course of therapy. Thepresent invention is directed to methods of treatment, prophylaxisand/or prevention of bacterial infections in a subject, such as a human,using one dose of oritavancin (or its pharmaceutically acceptable salts,hydrates, or solvates thereof, or a mixture thereof).

In a first embodiment, the present invention is directed to methods oftreating bacterial infections in a subject by administering one dose oforitavancin, or a pharmaceutically acceptable salt thereof, preferablyformulated as a pharmaceutical composition, over a course of therapy toa subject.

In a first aspect of this embodiment, the present invention is directedto a method of treating a bacterial infection in a subject, comprisingadministering one dose of a therapeutically effective amount of apharmaceutical composition comprising oritavancin, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier ordiluent, over a course of therapy to a subject having a bacterialinfection, thereby treating a bacterial infection in a subject. In apreferred aspect, the pharmaceutical composition comprises at leastabout 400 mg oritavancin, or a pharmaceutically acceptable salt thereof.In a further preferred aspect, the pharmaceutical composition comprisesbetween about 400 mg to about 1800 mg oritavancin, or a pharmaceuticallyacceptable salt thereof. In specific aspects, the pharmaceuticalcomposition comprises about 800 mg, 900 mg, 1000 mg, 1100 mg, or 1200 mgoritavancin, or a pharmaceutically acceptable salt thereof.

In a variation of this first aspect, a single subsequent dose oforitavancin may be administered to the subject. Thus, the method of thefirst aspect may further comprise administering a second dose of atherapeutically effective amount of a pharmaceutical compositioncomprising oritavancin, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier or diluent, within the courseof therapy. Preferably, the second dose comprises an amount oforitavancin less than or equal to that of the first dose. Alsopreferably, the second dose is administered about 4 days or more afterthe first dose.

In a second aspect of this embodiment, the present invention is directedto a method of treating a bacterial infection in a subject, comprisingadministering one dose of a pharmaceutical composition comprisingoritavancin, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or diluent, over a course of therapyto a subject having a bacterial infection, in an amount sufficient toachieve a maximum plasma concentration (C_(max)) of oritavancin of notless than about 20 μg/mL. In preferred aspects, the C_(max) oforitavancin is not less than about 40 μg/mL, 60 μg/mL, or 80 μg/mL.

In a variation of this second aspect, a single subsequent dose oforitavancin may be administered to the subject. Thus, the method of thesecond aspect may further comprise administering a second dose of atherapeutically effective amount of a pharmaceutical compositioncomprising oritavancin, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier or diluent, within the courseof therapy. Preferably, the second dose comprises an amount oforitavancin less than or equal to that of the first dose. Alsopreferably, the second dose is administered about 4 days or more afterthe first dose.

In a third aspect of this embodiment, the present invention is directedto a method of treating a bacterial infection in a subject, comprisingadministering one dose of a pharmaceutical composition comprisingoritavancin, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or diluent, over a course of therapyto a subject having a bacterial infection, in an amount sufficient toachieve an area under the concentration curve (AUC 0-24 hr) oforitavancin of at least about 20 μg*h/mL. In preferred aspects, the AUC0-24 hr of oritavancin is at least about 40 μg*h/mL, 80 μg*h/mL, or 120μg*h/mL.

In a variation of this third aspect, a single subsequent dose oforitavancin may be administered to the subject. Thus, the method of thethird aspect may further comprise administering a second dose of atherapeutically effective amount of a pharmaceutical compositioncomprising oritavancin, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier or diluent, within the courseof therapy. Preferably, the second dose comprises an amount oforitavancin less than or equal to that of the first dose. Alsopreferably, the second dose is administered about 4 days or more afterthe first dose.

In a second embodiment, the present invention is directed to methods ofproviding prophylaxis for bacterial infections in a subject byadministering one dose of oritavancin, or a pharmaceutically acceptablesalt thereof, preferably formulated as a pharmaceutical composition,over a course of therapy to a subject.

In an aspect of this embodiment, the present invention is directed to amethod of providing prophylaxis for a bacterial infection in a subject,comprising administering one dose of a therapeutically effective amountof a pharmaceutical composition comprising oritavancin, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or diluent, over a course of prophylaxis to a subjectat risk of developing a bacterial infection, thereby providingprophylaxis for a bacterial infection in a subject. In a preferredaspect, the pharmaceutical composition comprises at least about 200 mgoritavancin, or a pharmaceutically acceptable salt thereof. In a furtherpreferred aspect, the pharmaceutical composition comprises between about200 mg to about 1800 mg oritavancin, or a pharmaceutically acceptablesalt thereof. In specific aspects, the pharmaceutical compositioncomprises about 300 mg, 400 mg, 500 mg, 600 mg, 700 mg or 800 mgoritavancin, or a pharmaceutically acceptable salt thereof. In preferredaspects, prophylaxis is maintained for at least about 4, 8 or 12 hours.In an alternative aspect, prophylaxis is maintained is for the durationof a surgical procedure, a dental procedure or an invasive medicalprocedure.

In a variation of this aspect, a single subsequent dose of oritavancinmay be administered to the subject. Thus, the method of this embodimentmay further comprise administering a second dose of a therapeuticallyeffective amount of a pharmaceutical composition comprising oritavancin,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or diluent, within the course of therapy. Preferably,the second dose comprises an amount of oritavancin less than or equal tothat of the first dose.

In a third embodiment, the present invention is directed to methods ofpreventing bacterial infections in a subject by administering one doseof oritavancin, or a pharmaceutically acceptable salt thereof,preferably formulated as a pharmaceutical composition, over a course oftherapy to a subject.

In an aspect of this embodiment, the present invention is directed to amethod of preventing a bacterial infection in a subject, comprisingadministering one dose of a therapeutically effective amount of apharmaceutical composition comprising oritavancin, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier ordiluent, over a course of prevention to a subject at risk of exposure toinfectious bacteria, thereby preventing a bacterial infection in asubject. In a preferred aspect, the pharmaceutical composition comprisesat least about 400 mg oritavancin, or a pharmaceutically acceptable saltthereof. In a further preferred aspect, the pharmaceutical compositioncomprises between about 400 mg to about 1800 mg oritavancin, or apharmaceutically acceptable salt thereof. In specific aspects, thepharmaceutical composition comprises about 700 mg, 800 mg, 900 mg, 1000mg, 1100 mg or 1200 mg oritavancin, or a pharmaceutically acceptablesalt thereof. In preferred aspects, prevention is maintained is for atleast about 24, 72 or 114 hours.

In a variation of this aspect, a single subsequent dose of oritavancinmay be administered to the subject. Thus, the method of this embodimentmay further comprise administering a second dose of a therapeuticallyeffective amount of a pharmaceutical composition comprising oritavancin,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or diluent, within the course of therapy. Preferably,the second dose comprises an amount of oritavancin less than or equal tothat of the first dose.

Each of the methods of the present invention is preferably practicedwherein the administration of the pharmaceutical compositions is viaintravenous administration or oral administration.

The methods of the present invention include those where the bacterialinfection is a Complicated Skin and Skin Structure Infection (cSSSI).The methods of the present invention also include those where theinfectious bacteria and the bacteria causing a bacterial infection isselected from the group consisting of a gram-positive bacteria,Staphylococcus aureus, methicillin-resistant Staphylococcus aureus,vancomycin-resistant Staphylococcus aureus, vancomycin-intermediateStaphylococcus aureus, vancomycin hetero-intermediate Staphylococcusaureus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcusanginosus, Streptococcus intermedius, Streptococcus constellatus,Streptococcus dysgalactiae, Streptococcus dysgalactiae subsp.equisimilis, Streptococcus pneumoniae, Group A Streptococci species,Group B Streptococci species, Group C Streptococci species, Group DStreptococci species, Enterococci species, Enterococcus faecalis,vancomycin-resistant Enterococcus faecalis, Enterococcus faecium,vancomycin-resistant Enterococcus faecium, Staphylococcus epidermidis,methicillin-resistant Staphylococcus epidermidis, Staphylococcushaemolyticus, Bacillus anthracis and Clostridium difficile.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Clinical cure rates for Staphylococcus aureus by oritavancin MICin the microbiologically evaluable population at test-of-cure.

FIG. 2. Clinical cure rates for methicillin resistant Staphylococcusaureus by oritavancin MIC in the microbiologically evaluable populationat test-of-cure.

FIG. 3. Comparative single dose-response study of oritavancin againstMSSA and MRSA in the neutropenic-mouse thigh infection model. Infectioncaused by S. aureus ATCC13709 (MSSA) and NRS123 (MRSA). Similar ED₅₀:5.8 (3.3-10) and 2.4 (0.8-7.3) mg/kg for ATCC13709 and NRS123,respectively.

FIG. 4. Efficacy of HEQ dose of oritavancin in the neutropenic-mousethigh infection model (mean±SEM). Infection caused by S. aureusATCC13709. A dose-response relationship is observed with ≧2-Log kill for200, 400 and 1200 mg at 72 h.

FIG. 5. Efficacy of oritavancin against MSSA or MRSA strains in theneutropenic-mouse thigh infection model at 72 h post-infection (meanwith 95% CI). *p-value≦0.05 compared to the 200 mg HEQ dose. In vivoefficacy is not affected by the oxacillin resistance phenotype.Oritavancin was active against all tested strains, independently oftheir MIC.

FIG. 6. Histogram of oritavancin doses administered.

FIG. 7. Histogram of oritavancin infusion durations.

FIG. 8. Histogram of oritavancin infusion rates.

FIG. 9. Semilog scatterplot of oritavancin concentrations versus timesince start of last infusion, stratified by dose range, following asingle dose of oritavancin.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the discovery by the inventors thatoritavancin exhibits a prolonged plasma half-life. This discoverypermits single doses of the compound to be effective in the treatment,prophylaxis or prevention of bacterial infections in a subject.Accordingly, in a first embodiment the present invention is directed tomethods of treating a bacterial infection in a subject, comprisingadministering one dose of a therapeutically effective amount oforitavancin, or a pharmaceutically acceptable salt thereof, over acourse of therapy to a subject having a bacterial infection. Specificaspects of this embodiment are provided in the summary of the invention.

In a second embodiment the present invention is directed to methods ofproviding prophylaxis for a bacterial infection in a subject, comprisingadministering one dose of a therapeutically effective amount oforitavancin, or a pharmaceutically acceptable salt thereof, over acourse of therapy to a subject in need of prophylaxis. Specific aspectsof this embodiment are provided in the summary of the invention.

In third embodiment the present invention is directed to methods ofpreventing a bacterial infection in a subject, comprising administeringone dose of a therapeutically effective amount of oritavancin, or apharmaceutically acceptable salt thereof, over a course of therapy to asubject in need of prevention. Specific aspects of this embodiment areprovided in the summary of the invention.

In each embodiment, a second dose of a therapeutically effective amountof oritavancin, or a pharmaceutically acceptable salt thereof, may beadministered to the subject.

Preferably, in each embodiment of the invention oritavancin isadministered in the form of a pharmaceutical composition comprisingoritavancin, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or diluent.

Oritavancin (also termed N-(4-(4-chlorophenyl)benzyl)A82846B andLY333328) has the following chemical structure:

Oritavancin may be used per se in the methods of the present invention,or in the form of a pharmaceutically acceptable salt, hydrate, solvate,or mixtures thereof. The term “pharmaceutically acceptable salt” refersto non-toxic acid addition salts derived from inorganic and organicacids. While reference is made herein to both “oritavancin” and “apharmaceutically acceptable salt thereof”, the term “oritavancin” shouldbe understood to include both the compound per se as well as apharmaceutically acceptable salt, unless otherwise indicated by context,as the term “oritavancin” alone may be used for the sake of brevity.

Acids commonly employed to form acid addition salts are inorganic acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic acid, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like. Base addition salts includethose derived from inorganic bases, such as ammonium or alkali oralkaline earth metal hydroxides, carbonates, bicarbonates, and the like.Such bases useful in preparing the salts of this invention thus includesodium hydroxide, potassium hydroxide, ammonium hydroxide, potassiumcarbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate,calcium hydroxide, calcium carbonate, and the like. The potassium andsodium salt forms are particularly preferred.

It should be recognized that the particular counter-ion forming a partof any salt of this invention is not of a critical nature, so long asthe salt as a whole is pharmacologically acceptable and as long as thecounter-ion does not contribute undesired qualities to the salt as awhole.

Means for the preparation of the glycopeptide antibiotics, includingoritavancin and analogs thereof, may be found, for example, in U.S. Pat.No. 5,840,684, incorporated herein by reference in its entirety.

Pharmaceutical Compositions

In each of the methods of the present invention, oritavancin may beadministrated to the subject in the form of a pharmaceuticalcomposition. The pharmaceutical compositions of the invention compriseoritavancin, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or excipient.

Pharmaceutically acceptable carriers and excipient are those compounds,solutions, substances or materials that can be used to produceformulations of oritavancin that are suitable for administered to asubject, such as a human. In particular, carriers and excipients of thepresent invention are those useful in preparing a pharmaceuticalcomposition that is generally safe, non-toxic and neither biologicallynor otherwise undesirable, and that may present pharmacologicallyfavorable profiles, and includes carriers and excipient that areacceptable for veterinary use as well as human pharmaceutical use.Suitable pharmaceutically acceptable carriers and excipients are wellknown in art and can be determined by those of skill in the art as theclinical situation warrants. The skilled artisan will understand thatdiluents are included within the scope of the terms carriers andexcipients. Examples of suitable carriers and excipients includedextrose, water, glycerol, ethanol, propylene glycol, polysorbate 80(Tween-80™), poly(ethylene)glycol 300 and 400 (PEG 300 and 400),PEGylated castor oil (e.g. Cremophor EL), poloxamer 407 and 188, acyclodextrin or a cyclodextrin derivative (including HPCD((2-hydroxypropyl)-cyclodextrin) and (2-hydroxyethyl)-cyclodextrin; see,e.g., U.S. patent application publication 20060194717), hydrophilic andhydrophobic carriers, and combinations thereof. Hydrophobic carriersinclude, for example, fat emulsions, lipids, PEGylated phospholids,polymer matrices, biocompatible polymers, lipospheres, vesicles,particles, and liposomes. The terms specifically exclude cell culturemedium. More particularly: (1) 5% (w/v) dextrose, or (2) water, may beused as a pharmaceutically acceptable carrier.

Excipients included in a formulation have different purposes depending,for example on the nature of the drug, and the mode of administration.Examples of generally used excipients include, without limitation:stabilizing agents, solubilizing agents and surfactants, buffers,antioxidants and preservatives, tonicity agents, bulking agents,lubricating agents, emulsifiers, suspending or viscosity agents, inertdiluents, fillers, disintegrating agents, binding agents, wettingagents, lubricating agents, antibacterials, chelating agents,sweeteners, perfuming agents, flavouring agents, coloring agents,administration aids, and combinations thereof.

The compositions may contain common carriers and excipients, such ascornstarch or gelatin, lactose, sucrose, microcrystalline cellulose,kaolin, mannitol, dicalcium phosphate, sodium chloride, alginic acid,croscarmellose sodium, and sodium starch glycolate.

The particular carrier, diluent or excipient used will depend upon themeans and purpose for which the active ingredient is being applied.

Pharmaceutically acceptable excipients also include tonicity agents thatmake the composition compatible with blood. Tonicity agents areparticularly desirable in injectable formulations.

Acceptable methods for preparing the pharmaceutical compositionsaccording to the invention are known to those skilled in the art. Forexample, pharmaceutical compositions may be prepared followingconventional techniques of the pharmaceutical chemist involving stepssuch as mixing, granulating, and compressing when necessary for tabletforms, or mixing, filling, and dissolving the ingredients asappropriate, to give the desired products for various routes ofadministration.

Methods of Treatment, Prophylaxis and Prevention

The methods of the invention comprise contacting bacteria with aneffective amount of oritavancin, or a pharmaceutically acceptable saltthereof. For example, one can inhibit cell wall biosynthesis in agram-positive bacterium by contacting such a bacterium with oritavancin.The contacting may be carried out in vitro (in biochemical and/orcellular assays), in vivo in a non-human animal, in vivo in mammals,including humans and/or ex vivo (e.g. for sterilization purposes). Asused herein, the term “contacting” is meant to broadly refer to bringinga bacterial cell and a molecule of oritavancin into sufficient proximitysuch that oritavancin can exert an effect on the bacterial cell.Oritavancin may be transported to the location of the bacterial cell, ororitavancin may be situated in a location to which the bacterial celltravels or is brought into contact. The skilled artisan will understandthat the term “contacting” includes physical interaction betweenoritavancin and a bacterial cell, as well as interactions that do notrequire physical interaction.

As used herein, a “subject” means an animal, such as a mammal, includinghumans, other higher primates, lower primates, and animals of veterinaryimportance, such as dogs, cats, horses, sheep, goats, and cattle and thelike, preferably a human. The subject may have a bacterial infection,may be at risk for developing a bacterial infection, or may be atgreater risk than the general population for exposure to infectiousbacteria.

As used herein, “bacterial infection” refers to an infection caused by aspecies or strain of bacteria for which the single dosing methodsdisclosed herein are appropriate. For example, the methods of treatmentmay be used in the treatment of subjects having bacterial skininfections, such as complicated skin and skin structure infections(cSSSI) and complicated and uncomplicated skin and soft tissueinfections (SSTI), including abscesses, ulcers, burns and cellulitis.The methods of treatment also include treatment of deep bacterialinfections, such as major abscess, infected ulcer, major burn, or deepand extensive cellulitis. Further bacterial infections that may betreated using the methods of the present invention include blood streaminfections (BSI), catheter-related blood stream infections (CRBSI),osteomyelitis, prosthetic joint infections, pneumonia (communityacquired and nosicomial), joint space infections and device infections(e.g., infections associated with pace makers and internal cardiacdefibrillators). The methods of treatment can also be practicedconcomitantly with surgical intervention for the bacterial infection.

The infectious bacteria and those bacteria causing bacterial infectionsinclude those described in U.S. Pat. No. 5,840,684, gram-positivebacteria, and in particular, Staphylococcus aureus(methicillin-susceptible and -resistant strains; vancomycin-susceptible,-intermediate, -hetero-intermediate and -resistant strains),Streptococcus pyogenes, Streptococcus agalactiae, Streptococcusanginosus grp. (including S. anginosus, S. intermedius, and S.constellatus), Streptococcus dysgalactiae (including S. dysgalactiaesubsp. equisimilis), Streptococcus pneumoniae, Streptococci species,including Streptococci Group A species, Streptococci Group B species,Streptococci Group C species, and Streptococci Group D species,Enterococci species, Enterococcus faecalis (vancomycin-susceptible and-resistant strains), Enterococcus faecium (vancomycin-susceptible and-resistant strains), Staphylococcus epidermidis (methicillin-susceptibleand -resistant strains), Staphylococcus haemolyticus, Bacillusanthracis, and Clostridium difficile (both vegetative form and spores).

Methods of Treating

As discussed in the summary of the invention above, in a firstembodiment the invention is directed to methods of treating bacterialinfections in a subject by administering one dose of oritavancin, or apharmaceutically acceptable salt thereof, preferably formulated as apharmaceutical composition, over a course of therapy to a subject. Thus,the invention includes methods of treating a bacterial infection in asubject, comprising administering one dose of a therapeuticallyeffective amount of a pharmaceutical composition comprising oritavancin,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or diluent, over a course of therapy to a subjecthaving a bacterial infection, thereby treating a bacterial infection ina subject. In an aspect of this embodiment, a second dose of thepharmaceutical composition may be administered to the subject.

The methods of treatment of the present invention may also be based onachieving a particular pharmacokinetic profile for oritavancin in asubject (Bhavnani et al., Antimicrobial Agents Chemother. 50(3):994-1000(2006)). For example, the invention includes methods of treatingbacterial infections in a subject, comprising administering one dose oforitavancin, or a pharmaceutically acceptable salt thereof, preferablyformulated as a pharmaceutical composition, sufficient to achieve one ormore of: (1) a maximum plasma concentration (C_(max)) of oritavancin ofnot less than a selected level, or (2) a minimum area under theconcentration curve (AUC 0-24 hr) of at least a selected level.

Thus the invention also includes methods of treating a bacterialinfection in a subject, comprising administering one dose of apharmaceutical composition comprising oritavancin, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier ordiluent, over a course of therapy to a subject having a bacterialinfection, in an amount sufficient to achieve a maximum plasmaconcentration (C_(max)) of oritavancin of not less than a selectedvalue. In an aspect of this embodiment, a second dose of thepharmaceutical composition may also be administered to the subject.

It will be understood that a therapeutically effective minimum C_(max)of oritavancin will vary based on the concentration of oritavancin inthe formulation being administered to a subject, the means ofadministration, the duration of administration, the type of bacterialinfection being treated and the identity of the bacteria in theinfection, among other factors such as the physical characteristics ofthe subject. However, under most circumstances a minimum C_(max) of notless than about 1 μg/mL should be achieved in a subject. Thus, thepresent invention includes achieving a minimum C_(max) of not less thanabout 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80,85, 90, 95 or 100 μg/mL in the subject. In preferred aspects, theC_(max) of oritavancin is not less than about 20 μg/mL. In otherpreferred aspects, the C_(max) of oritavancin is not less than about 40μg/mL, 60 μg/mL, or 80 μg/mL.

The invention further includes methods of treating a bacterial infectionin a subject, comprising administering one dose of a pharmaceuticalcomposition comprising oritavancin, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier or diluent, overa course of therapy to a subject having a bacterial infection, in anamount sufficient to achieve an area under the concentration curve (AUC0-24 hr) of oritavancin of at least a selected value. In an aspect ofthis embodiment, a second dose of the pharmaceutical composition mayalso be administered to the subject.

It will be understood that a therapeutically effective minimum AUC 0-24hr of oritavancin will vary based on the concentration of oritavancin inthe formulation being administered to a subject, the means ofadministration, the duration of administration, the type of bacterialinfection being treated and the identity of the bacteria in theinfection, among other factors such as the physical characteristics ofthe subject. However, under most circumstances a minimum AUC 0-24 hr ofat least about 20 μg*h/mL should be achieved in a subject. Thus, thepresent invention includes achieving a minimum AUC of not less thanabout 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,100, 105, 110, 115, 120, 125, 130, 135, 140, 145 or 150 μg*h/mL in thesubject. In preferred aspects, the AUC 0-24 hr of oritavancin is atleast about 20 μg*h/mL. In other preferred aspects, the AUC 0-24 hr oforitavancin is at least about 40 μg*h/mL, 80 μg*h/mL, or 120 μg*h/mL.

The terms “treating” and “treatment” mean at least the mitigation of adisease condition or symptom associated with a bacterial infection in asubject that is achieved by a reduction of growth, replication, and/orpropagation, or death or destruction of bacteria, on or in the subject.The terms “treating” and “treatment” include curing, healing,inhibiting, relieving from, improving and/or alleviating, in whole or inpart, the disease condition. The mitigation of a disease condition orsymptom may be about 100%, 99%, 98%, 97%, 96%, 95%, 90%, 80%, 70%, 60%,50%, 40%, 30%, 20%, 10%, 5% or 1% in the subject, versus a subject towhich oritavancin has not been administered. In one aspect, treatingmeans reducing the population of bacteria causing the infection in thesubject to an undetectable level, where detection is by any conventionalmeans, such culturing a sample in the laboratory. In another aspect,treating means complete healing of the infection, shown by an absence ofclinical symptoms associated with the infection. In further aspect ofthe invention, treating means the mitigation of a disease condition orsymptom by at least about 90% in the subject. In an additional aspect,treating means the mitigation of a disease condition or symptom by atleast about 95% in the subject.

The therapeutically effective amount of oritavancin and the amountsufficient to achieve the stated goals of the methods of treatmentdisclosed herein in each dosage will vary, for example, in view of thephysical characteristics of the subject, the severity of the subject'ssymptoms, the form of the infection, the identity of the bacteria, theformulation and the means used to administer the drug, and the methodbeing practiced. The specific dose for a given subject is usually set bythe judgment of the attending physician. However, in each dose atherapeutically effective amount of oritavancin is typically at leastabout 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800,850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400,1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950 or 2000mg oritavancin. In specific aspects, in each dose a therapeuticallyeffective amount of oritavancin is between about 100 mg and 3000 mgoritavancin, preferably about 200, 250, 300, 350, 400, 450, 500, 550,600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200,1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800,1850, 1900, 1950 or 2000 mg oritavancin.

In a preferred aspect, the dose contains at least about 400 mgoritavancin. In a further preferred aspect, the dose contains betweenabout 400 mg to about 1800 mg oritavancin. In specific aspects, the dosecontains about 800, 900, 1000, 1100 or 1200 mg oritavancin.

Depending on the means of administration, the dosage may be administeredall at once, such as with an oral formulation in a capsule, or slowlyover a period of time, such as with an intravenous administration. Forslower means of administration, the administering period can be a matterof minutes, such as about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60,65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 or more minutes, ora period of hours, such as about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5or more hours. The administration of the dose may be interrupted, suchas where the dose is administered via intravenous infusion and the doseis divided into two or more infusion bags. Under such circumstances, theadministration of the dose may be interrupted while the infusion bagsare changed.

Methods of Prophylaxis

In a second embodiment, the invention is directed to methods ofproviding prophylaxis for bacterial infections in a subject byadministering one dose of oritavancin, or a pharmaceutically acceptablesalt thereof, preferably formulated as a pharmaceutical composition overa course of therapy to a subject. Thus, the invention includes a methodof providing prophylaxis for a bacterial infection in a subject,comprising administering one dose of a therapeutically effective amountof a pharmaceutical composition comprising oritavancin, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or diluent, over a course of prophylaxis to a subjectat risk of developing a bacterial infection, thereby providingprophylaxis for a bacterial infection in a subject. In an aspect of thisembodiment, a second dose of the pharmaceutical composition may beadministered to the subject.

Many physicians believe that humans should be considered for antibioticprophylaxis before a surgical procedure, a dental procedure or invasivemedical procedure to mitigate the potential for an infection resultingfrom ineffective sterility during the procedure. Deep infection is aserious complication sometimes requiring subsequent medicalinterventions and is accompanied by significant morbidity and mortality.Oritavancin may therefore be used as a replacement for, or in additionto, prophylactic antibiotics in this situation. For instance,oritavancin and/or pharmaceutical compositions of the invention may beadministered to a subject to achieve a systemic and/or local effectagainst relevant bacteria shortly before an invasive medical treatment,such as surgery or insertion of an in-dwelling device (e.g. jointreplacement (hip, knee, shoulder, etc.)). Treatment may be repeatedafter the invasive medical treatment, such as post-operatively or duringthe in-body time of the device.

The term “prophylaxis” means a reduction in the likelihood that adisease condition associated with a bacterial infection will develop ina subject, preferably a human. In particular, the term is related to theadministration of oritavancin to a subject to reduce the likelihood ofthe occurrence of a bacterial infection, such as bacterial infectionthat may occur during or following a surgery, a dental procedure orinvasive medical procedure. For example, one can reduce the likelihoodof a bacterial infection in a subject by administering oritavancinbefore exposure to bacteria. The prophylaxis may be about a reduction ofat least about 100%, 99%, 98%, 97%, 96%, 95%, 90%, 80%, 70%, 60%, 50%,40%, 30%, 20%, 10%, 5% or 1% in the subject, versus a subject to whichoritavancin has not been administered. The prophylaxis may last in thesubject for at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 22, 23 or 24 hours, or 2, 3, 4, 5, 6, 7,8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30 or more days afteradministration of oritavancin. In an alternative aspect, prophylaxis ismaintained for the duration of a surgical procedure, a dental procedureor an invasive medical procedure.

In preferred aspects, prophylaxis (i.e., a reduction in the likelihoodthat a disease condition associated with a bacterial infection willdevelop in a subject) is maintained for at least about 4, 8 or 12 hours.In one particular aspect, the reduction in the likelihood that a diseasecondition associated with a bacterial infection will develop in asubject is a reduction of at least about 90% for at least about 4 hours.In another particular aspect, the reduction in the likelihood that adisease condition associated with a bacterial infection will develop ina subject is a reduction of at least about 95% for at least about 4hours.

Oritavancin or a pharmaceutical composition comprising the compound maybe administered within 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 day, or within24, 22, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0.5 hourprior to when a subject will potentially be exposed to bacteria, such aprior to surgery or a dental procedure, thereby permitting an advisablesystemic or local presence of oritavancin, preferably in the areaspotentially exposed to bacterial contamination during the surgicalprocedure.

The therapeutically effective amount of oritavancin in each dosage forprophylaxis will vary depending, for example, upon the physicalcharacteristics of the subject, the procedure to which the subject willbe subjected, the identity of the bacteria that could potentially causeinfection, the formulation and the means used to administer the drug.The specific dose for a given subject is usually set by the judgment ofthe attending physician. However, in each dose a therapeuticallyeffective amount of oritavancin is typically at least about 200, 250,300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950,1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550,1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950 or 2000 mg oritavancin.In specific aspects, in each dose a therapeutically effective amount oforitavancin is between about 100 mg and 3000 mg oritavancin, preferablyabout 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800,850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400,1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950 or 2000mg oritavancin.

In a preferred aspect, the dose contains at least about 200 mgoritavancin. In a further preferred aspect, the dose contains betweenabout 200 mg to about 1800 mg oritavancin. In specific aspects, the dosecontains about 300, 400, 500, 600, 700 or 800 mg oritavancin.

Depending on the means of administration, the dosage may be administeredall at once, such as with an oral formulation in a capsule, or slowlyover a period of time, such as with an intravenous administration. Forslower means of administration, the administering period can be a matterof minutes, such as about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60,65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 or more minutes, ora period of hours, such as about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5or more hours. The administration of the dose may be interrupted, suchas where the dose is administered via intravenous infusion and the doseis divided into two or more infusion bags. Under such circumstances, theadministration of the dose may be interrupted while the infusion bagsare changed.

Methods of Preventing

In a third embodiment, the invention is directed to methods ofpreventing bacterial infections in a subject by administering one doseof oritavancin, or a pharmaceutically acceptable salt thereof,preferably formulated as a pharmaceutical composition, over a course oftherapy to a subject. Thus, the invention includes a method ofpreventing a bacterial infection in a subject, comprising administeringone dose of a therapeutically effective amount of a pharmaceuticalcomposition comprising oritavancin, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier or diluent, overa course of prevention to a subject at risk of exposure to infectiousbacteria, thereby preventing a bacterial infection in a subject. In anaspect of this embodiment, a second dose of the pharmaceuticalcomposition may be administered to the subject.

The terms “prevent” and “prevention” mean blocking or stopping a diseasecondition associated with a bacterial infection from developing in asubject, preferably a human. Such methods may be practiced, for example,on subjects having a higher risk for bacterial infection than thegeneral population, including patients undergoing treatment forbacterial infections whereby normal gut flora is inhibited byantimicrobial therapy, patients with impaired immune function (e.g.,immunoglobulin deficiency, splenic dysfunction, splenectomy, HIVinfection, impaired leukocyte function, hemoglobinopathies), the elderly(Loo et al., 2005. NEJM 353:2442), people with certain malignancies(e.g., multiple myeloma, chronic lympocytic leukemia, lymphoma), peopleat increased occupational risk (e.g., public services workers, such afire, water, sanitary, police, medical, and laboratory workers, hospitalworkers), people in closed populations (e.g., prisons, military, nursinghomes) and others that have immunological deficiencies that mightenhance their susceptibility to bacterial infection. The prevention maylast in the subject for at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50 ormore days after administration of oritavancin.

In one aspect of the invention, the prevention lasts at least about 24hours in the subject. In another aspect, the prevention lasts at leastabout 72 hours in the subject. In further aspect, the prevention lastsat least about 144 hours in the subject.

Oritavancin or a pharmaceutical composition comprising the compound maybe administered within 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 day, or within24, 22, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or 0.5 hourprior to when a subject will potentially be exposed to bacteria, suchprior to contact by military personnel with a material suspected ofcontaining a particular bacteria.

The therapeutically effective amount of oritavancin in each dosage forprevention will vary depending, for example, upon the physicalcharacteristics of the subject, the identity of the bacteria to whichthe subject may be exposed, the formulation and the means used toadminister the drug. The specific dose for a given subject is usuallyset by the judgment of the attending physician. However, in each dose atherapeutically effective amount of oritavancin is typically at leastabout 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800,850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400,1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950 or 2000mg oritavancin. In specific aspects, in each dose a therapeuticallyeffective amount of oritavancin is between about 100 mg and 3000 mgoritavancin, preferably about 200, 250, 300, 350, 400, 450, 500, 550,600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200,1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800,1850, 1900, 1950 or 2000 mg oritavancin.

In a preferred aspect, the dose contains at least about 400 mgoritavancin. In a further preferred aspect, the dose contains betweenabout 400 mg to about 1800 mg oritavancin. In specific aspects, the dosecontains about 700, 800, 900, 1000, 1100 or 1200 mg oritavancin.

Depending on the means of administration, the dosage may be administeredall at once, such as with an oral formulation in a capsule, or slowlyover a period of time, such as with an intravenous administration. Forslower means of administration, the administering period can be a matterof minutes, such as about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60,65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120 or more minutes, ora period of hours, such as about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5or more hours. The administration of the dose may be interrupted, suchas where the dose is administered via intravenous infusion and the doseis divided into two or more infusion bags. Under such circumstances, theadministration of the dose may be interrupted while the infusion bagsare changed.

Second Dose

Under some circumstances, a second dose of oritavancin may be requiredto be administered to achieve the goal of a given method. For example,an attending physician may determine that one dose of oritavancin hasnot been sufficient to achieve full treatment of a particular bacterialinfection in a patient.

When a second dose is administered to a subject within the course oftherapy, preferably the amount of oritavancin in the second dose is thesame as or less than the amount administered to the patient in the firstdose. In specific embodiments, the amount of oritavancin in the seconddose is 100% or less, 90% or less, 80% or less, 70% or less, 60% orless, 50% or less, 40% or less, 30% or less, 20% or less, or 10% or lessthan the amount of oritavancin in the first dose.

When a second dose is administered over the course of therapy, the delaybetween doses will vary based on the same considerations discussedherein concerning the amount of oritavancin to be included in a dose.The delay can be determined by the attending physician. In generalhowever, when the method being practiced is a method of treatment, thedelay between the doses may be about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4,4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10 days, preferably about4 days. When the method being practiced is a method of prophylaxis, thedelay between the doses may be about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4,4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10 hours. When the methodbeing practiced is a method of prevention, the delay between the dosesmay be about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8,8.5, 9, 9.5 or 10 days.

Where two or more doses of oritavancin are being administered over thecourse of therapy, the individual doses may be administered in the samemanner and/or formulation, or in different manners and/or formulations.

As used herein, the terms “dose”, “unit dose”, “dosage”, “effectivedose” and related terms refer to physically discrete units that containa predetermined quantity of active ingredient calculated to produce adesired therapeutic effect. A single dose is thus a predeterminedquantity of oritavancin that is administered to a subject. Preferably,as disclosed in the methods of the invention, the oritavancin isformulated as a pharmaceutical composition for administration to thesubject.

As used herein, the term “course of therapy” depends on the particularmethod of the invention, however the term generally means the period oftime within which or over which a selected goal is achieved. In terms ofmethods of treatment, the course of therapy is the time period which isrequired to achieve treatment of the bacterial infection in the subject.In terms of methods of prophylaxis, the course of therapy is the periodof time over which prophylaxis for a bacterial infection is achieved. Interms of methods of prevention, the course of therapy is the period oftime over which prevention from a bacterial infection is achieved.

Although the invention is preferably directed to the treatment,prevention and/or prophylaxis of bacterial infections, the inventionencompasses therapeutic and prophylactic methods against other diseasescaused by or related to bacterial infection, including but not limitedto otitis, conjunctivitis, pneumonia, bacteremia, sinusitis, pleuralempyema and endocarditis, intravascular or endothelial infections,osteomyelitis and meningitis. In such methods, one dose of oritavancinis administered to a subject in an amount sufficient to provide atherapeutic effect and thereby prevent or treat the infection of thesubject.

The pharmaceutical compositions and compounds of the present inventionmay be formulated, for example, for oral, enteral, sublingual,intranasal, intraocular, rectal, intravaginal, transdermal, mucosal,topical or parenteral administration. Parenteral modes of administrationinclude without limitation, intradermal, subcutaneous (s.c., s.q.,sub-Q, Hypo), intramuscular (i.m.), intravenous (i.v.), intraperitoneal(i.p.), intra-arterial, intramedullary, intracardiac, intra-articular(joint), intrasynovial (joint fluid area), intracranial, intraspinal,and intrathecal (spinal fluids). Any known device useful for parenteralinjection or infusion of drug formulations can be used to effect suchadministration.

For topical use, the pharmaceutical compositions of present inventioncan be prepared in suitable forms to be applied to the skin, or mucusmembranes of the nose and throat, vagina or rectum, and can take theform of creams, ointments, suppositories, nasal drops, liquid sprays orinhalants, lozenges, or throat paints. Such topical formulations furthercan include chemical compounds such as dimethylsulfoxide (DMSO) tofacilitate surface penetration of the active ingredient. For applicationto the eyes or ears, the pharmaceutical compositions can be presented inliquid or semi-liquid form formulated in hydrophobic or hydrophilicbases as ointments, creams, lotions, paints or powders. For rectaladministration the pharmaceutical compositions can be administered inthe form of suppositories admixed with conventional carriers such ascocoa butter, wax or other glyceride.

Formulations for parenteral administration can be in the form of aqueousor non-aqueous isotonic sterile solutions, suspensions or fat emulsions.The unit dosage of these solutions or suspensions can be in aconcentrated liquid, powder or granular form for ex temporereconstitution in the appropriate pharmaceutically acceptable carrier,such as sterile water, at the time of delivery. In addition to theabove-mentioned excipients, powder forms optionally include bulkingagents (e.g. mannitol, glycine, lactose, sucrose, trehalose, dextran,hydroxyethyl starch, ficoll and gelatin), and cryo or lyoprotectants. Inan alternative embodiment, the parenteral unit dosage form ofpharmaceutical compositions and compounds of the present invention canbe a ready-to-use solution of the pharmaceutical compositions andcompounds in a suitable carrier in sterile, hermetically sealed ampoulesor in sterile pre-loaded syringes. The suitable carrier optionallycomprises any of the above-mentioned excipients. The parenteral formused for injection must be fluid to the extent that easy syringabilityexists.

Excipients used in parenteral preparations may also include, withoutlimitation, stabilizing agents (e.g. carbohydrates, amino acids andpolysorbates, such as 5% dextrose), solubilizing agents (e.g. cetrimide,sodium docusate, glyceryl monooleate, polyvinylpyrolidone (PVP) andpolyethylene glycol (PEG)), surfactants (e.g. polysorbates, tocopherolPEG succinate, poloxamer and Cremophor™), buffers (e.g. acetates,citrates, phosphates, tartrates, lactates, succinates, amino acids andthe like), antioxidants and preservatives (e.g. BHA, BHT, gentisicacids, vitamin E, ascorbic acid, sodium ascorbate and sulfur containingagents such as sulfites, bisulfites, metabisulfites, thioglycerols,thioglycolates and the like), tonicity agents (for adjustingphysiological compatibility), suspending or viscosity agents,antibacterials (e.g. thimersol, benzethonium chloride, benzalkoniumchloride, phenol, cresol and chlorobutanol), chelating agents, andadministration aids (e.g. local anesthetics, anti-inflammatory agents,anti-clotting agents, vaso-constrictors for prolongation and agents thatincrease tissue permeability), and combinations thereof.

Parenteral formulations using hydrophobic carriers include, for example,fat emulsions and formulations containing lipids, lipospheres, vesicles,particles and liposomes. Fat emulsions include in addition to theabove-mentioned excipients, a lipid and an aqueous phase, and additivessuch as emulsifiers (e.g. phospholipids, poloxamers, polysorbates, andpolyoxyethylene castor oil), and osmotic agents (e.g. sodium chloride,glycerol, sorbitol, xylitol and glucose). Liposomes include natural orderived phospholipids and optionally stabilizing agents such ascholesterol.

In intravenous (IV) use, a sterile formulation of the pharmaceuticalcompositions of the present invention and optionally one or moreadditives, including solubilizers or surfactants, can be dissolved orsuspended in any of the commonly used intravenous fluids andadministered by infusion. Intravenous fluids include 5% dextrose inwater.

In intramuscular preparations, a sterile formulation of thepharmaceutical compositions of the present invention can be dissolvedand administered in a pharmaceutical diluent such as Water-for-Injection(WFI) or 5% dextrose in water. A suitable insoluble form of thepharmaceutical compositions may be prepared and administered as asuspension in an aqueous base or a pharmaceutically acceptable oil base,e.g. an ester of a long chain fatty acid such as ethyl oleate.

For oral use, the oral pharmaceutical composition may be made in theform of a unit dosage containing a therapeutically-effective amount ofthe pharmaceutical compositions. Solid formulations such as tablets andcapsules are particularly useful. Sustained released or entericallycoated preparations may also be devised. For pediatric and geriatricapplications, suspension, syrups and chewable tablets are especiallysuitable. For oral administration, the pharmaceutical compositions arein the form of, for example, tablets, capsules, suspensions or liquidsyrups or elixirs, wafers and the like. For general oral administration,excipient or additives include, but are not limited to inert diluents,fillers, disintegrating agents, binding agents, wetting agents,lubricating agents, sweetening agents, flavoring agents, coloring agentsand preservatives.

The tablets and capsules can contain, in addition to the glycopeptideantibiotics, conventional carriers such as: inert diluents (e.g., sodiumand calcium carbonate, sodium and calcium phosphate, and lactose),binding agents (e.g., acacia gum, starch, gelatin, sucrose,polyvinylpyrrolidone (Povidone), sorbitol, tragacanth methylcellulose,sodium carboxymethylcellulose, hydroxypropyl methylcellulose, andethylcellulose), fillers (e.g., calcium phosphate, glycine, lactose,maize-starch, sorbitol, or sucrose), wetting agents, lubricating agents(e.g., metallic stearates, stearic acid, polyethylene glycol, waxes,oils, silica and colloical silica, silicon fluid or talc),disintegrating agents (e.g., potato starch, corn starch and alginicacid), flavouring (e.g. peppermint, oil of wintergreen, fruit flavoring,cherry, grape, bubblegum, and the like), and coloring agents. Carriersmay also include coating excipients such as glyceryl monostearate orglyceryl distearate, to delay absorption in the gastrointestinal tract.

Oral liquid preparations, generally in the form of aqueous or oilysolutions, suspensions, emulsions or elixirs, may contain conventionaladditives such as suspending agents, emulsifying agents, non-aqueousagents, preservatives, coloring agents and flavoring agents. Examples ofadditives for liquid preparations include acacia, almond oil, ethylalcohol, fractionated coconut oil, gelatin, glucose syrup, glycerin,hydrogenated edible fats, lecithin, methyl cellulose, microcrystallinecellulose, methyl or propyl para-hydroxybenzoate, propylene glycol,sorbitol, or sorbic acid. In one embodiment, the compounds may beformulated in 10% hydroxypropyl beta-cyclodextrin. In a furtherembodiment the compounds may be formulated in 85% polyethylene glycol400 (PEG400) in sterile water. The oral formulation may be in the formof a liquid to be drunk by the subject, in the form of a capsulecontaining the formulation, or other means known to the skilled artisanfor administering an oral formulation.

While the treatment can be administered in a systemic manner through themeans described above, it may also be administered in a localizedmanner. For example, the treatment may be administered directly, such asthrough a topical composition or directly into a subcutaneous or otherform of wound.

Each of the methods of the present invention may also be practiced byadministering a second therapeutic agent to the subject. Such secondtherapeutic agents may be included in a pharmaceutical formulationcomprising oritavancin, or they may be administered separately. A widerange of second therapeutic agents, such as antibiotics, can be used incombination with the compounds, compositions and methods of the presentinvention. Antibiotics used as second therapeutic agents may act byinterfering with cell wall synthesis, plasma membrane integrity, nucleicacid synthesis, ribosomal function, folate synthesis, etc. Anon-limiting list of useful antibiotics includes: fusidic acid,trimethoprim, sulfadiazine, sulfamethoxazole, a penicillin, amonobactam, a penam, a penem, a clavam, a clavem, a carbopenam, acarbopenem, a cepham, a cephem, an oxacepham, an oxacephem, acarbocepham, a carbocephem, a cephalosporin, tetracycline, atetracycline derived antibacterial agent, glycylcycline, a glycylcyclinederived antibacterial agent, minocycline, a minocycline derivedantibacterial agent, sancycline, a sancycline derived antibacterialagent, methacycline, a methacycline derived antibacterial agent, anoxazolidinone antibacterial agent, an aminoglycoside antibacterialagent, an additional glycopeptide or lipoglycopeptide, a quinoloneantibacterial agent, daptomycin, a daptomycin derived antibacterialagent, rifamycin, a rifamycin derived antibacterial agent, rifampin, arifampin derived antibacterial agent, rifalazil, a rifalazil derivedantibacterial agent, rifabutin, a rifabutin derived antibacterial agent,rifapentin, a rifapentin derived antibacterial agent, rifaximin and arifaximin derived antibacterial agent.

The second therapeutic agent may be administered before, concurrentlywith, or after a pharmaceutical formulation of the present invention isadministered to a subject.

The present invention also includes a kit comprising one or two doses ofa pharmaceutical composition comprising oritavancin and writteninstructions for its use in treatment, prophylaxis and/or prevention ofa bacterial infection, in a suitable container.

EXAMPLES Example 1

Oritavancin (Ori) is a semisynthetic lipoglycopeptide with demonstratedefficacy against gram-positive cSSSI including MRSA, when given 200 mgIV daily for 3-7 days (D) in a multi-dose (MD) fashion. Animal & phase 2& 3 PK data suggest potential for single dose (SD) or infrequent doses(ID) of On as potentially efficacious for cSSSI.

A phase 2, multi-center, randomized, double-blind, parallel,active-comparator study in which three dose regimens of oritavancin wereexplored as a treatment for cSSSI due to gram-positive pathogens wasconducted using: a daily dose (200 mg) administered for three to sevendays, a single dose (1200 mg), and an infrequent dose (800 mg dose withoption for an additional 400 mg on Day 5).

Study Design and Treatment.

Patients were randomized through an interactive voice response system ina 1:1:1 ratio to receive either 1) oritavancin comparator daily dose:200 mg IV daily for 3 to 7 days as determined by the investigator basedon clinical criteria, 2) oritavancin single dose: 1200 mg oritavancin IVon Day 1, or; 3) oritavancin infrequent dose: 800 mg IV on Day 1 withoptional 400 mg IV on Day 5 as determined by investigator based onclinical criteria. During randomization patients were stratified bydisease categories of wound infection, major abscess, and cellulitis.Placebo IV (5% dextrose in water) was given to maintain the blind.

Inclusion and exclusion criteria.

Patients were enrolled in the study if they had a cSSSI, presumed orproven to be caused by gram-positive pathogen(s), that met diseasediagnostic criteria (listed below and separated by disease state), were≧18 years of age, and had a body mass index≧17 kg/m² and ≦40 kg/m².

For the skin and skin structure infection to be classified ascomplicated one or more of the following criteria had to be met: 1)infection required significant surgical intervention within 48 hoursbefore or after enrollment; 2) infection process was suspected orconfirmed to involve deeper soft tissue, not fascia and/or musclelayers, or; 3) significant underlying disease was present thatcomplicated the response to treatment including, but not limited todiabetes mellitus, bacteremia, corticosteroid therapy or any levels ofneutropenia.

Additional criteria had to be met for each of the three categories ofinfection (wound infection, major abscess, cellulitis). Wound infectionsmust have had purulent drainage from the wound or ulcer, but not fromthe organ/space component of the injury and one or more of thefollowing: systemic manifestation of infection with fever (>38° C.) orleukocytosis (WBC>10,000/mm³ or a differential count showing >10% bandforms); localized pain or tenderness; erythema; or localized swelling.Major abscesses must have had acute onset within 7 days prior toenrollment, purulent drainage or purulent aspirate, systemicmanifestations of infection with fever or leukocytosis; erythema orinduration (≧2 cm in diameter) or tenderness; and evidence of loculatedfluid by physical examination, blind aspiration, or ultrasound thatrequired intervention (e.g., aspiration, incision and drainage,excision) within 48 hours of enrollment. Cellulitis must have had acuteonset within 7 days prior to enrollment; pain or tenderness; cutaneouserythema; advancing edema or induration; and history of fever within 3days prior to enrollment.

Patients were excluded from the study if they received any systemicantimicrobial agent with gram-positive coverage for more than 24 hourswithin the 3 days prior to enrollment (unless the gram-positive pathogenwas resistant in vitro to the antimicrobial agent or the patient wasclinically failing on prior therapy), had a history of severehypersensitivity reactions to glycopeptides and any of their excipients(patients who had histamine-like infusion reactions to the glycopeptidevancomycin were not excluded) or had an anticipated need for more than10 days of conventional antibiotic therapy. Pregnant women or women whowere nursing were also excluded from the study.

Analysis Populations.

Analyses were performed on four patient populations: intent-to-treat(ITT), modified intent-to-treat (MITT), clinically evaluable (CE) andmicrobiologically evaluable (ME). The ITT population included patientswho were randomized to treatment and received any amount of studymedication. Two patients who were potentially unblinded were excludedfrom the ITT population for all efficacy analyses. The MITT populationincluded all ITT patients with a gram-positive pathogen isolated atbaseline. The CE population included efficacy ITT patients who metenrollment criteria, received ≧80% of the intended study drug dose inthe intended timeframe based on assignment to treatment group, did nothave a clinical response of indeterminate at the end-of therapy or firstfollow-up assessment, had a first follow-up assessment of cure, failure,or improvement, or had a clinical response of failure at end-of-therapy.Patients in the ME population were CE patients who had a gram-positivepathogen isolated at baseline.

Clinical and Microbiologic Assessments.

The primary efficacy endpoint was the clinical response in the CEpopulation at TOC, which occurred 20 to 28 days after study enrollmenton Day 1. Clinical response was determined by the investigator as partof the end-of-therapy, TOC, and late follow-up procedures by assessingsigns and symptoms including fever, pain, tenderness, erythema,induration, edema, purulent drainage, eschar, and devitalized tissue. Aclinical response of cure, improvement, failure, or indeterminate wasassigned at end-of-therapy and TOC by the investigator based on clinicalsigns and symptoms. At late follow-up, the investigator could assign theclinical response of relapse in addition to cure, improvement, orindeterminate. Only patients with a clinical response of cure orimprovement at TOC were assessed for clinical response at latefollow-up.

Cure was defined as resolution of purulent drainage, pain, edema, fever,erythema, tenderness, and induration. Serous drainage or aspirate and/orgranulation tissue could be present Improvement was defined asresolution of purulent drainage and, in the case of cellulitis,cessation of fever and pain. Residual erythema, edema, pain (in the caseof wound or abscess), tenderness, and/or induration could be present ascould serous drainage, granulation tissue, eschar, and/or devitalizedtissue. Failure included any of the following: presence of purulentdrainage (or aspirate) and/or fever; the unanticipated need for abscessdrainage or removal of sutures (for treatment of infection)>48 hoursafter initiation of study therapy; or treatment with nonstudy systemicantibiotic having activity against gram-positive pathogen(s) for theprimary infection site or use of topical antibiotics at the site ofprimary infection 24 hours or more after initiation of study medicationtherapy.

Blood and infection site cultures were obtained within three days ofenrollment (often done at the time of enrollment). End-of-therapy, TOC,and late follow-up (or at early relapse) cultures were obtained from theinfection site if clinically indicated. If a patient proved to havebacteremia at baseline, follow-up blood cultures were performed at aminimum at end-of-therapy and TOC. Specimens were cultured and pathogenswere identified at each investigative site's certified laboratory. Allisolated gram-positive pathogen(s) that were obtained from the infectionsite at baseline/randomization and up to and including the TOC timepoint were subcultured and sent to a central laboratory (CovanceClinical Laboratories, Indianapolis, Ind.) for confirmatoryidentification and susceptibility testing. In cases of discrepancybetween the local and the central laboratory, central laboratory resultswere used.

Statistical Analysis.

The primary hypothesis was that oritavancin single or infrequent doseswere non-inferior to oritavancin daily doses. The primary efficacyendpoint was clinical response (either cure or improvement versusfailure) at TOC in the CE population. The primary efficacy analyses werea comparison of the proportions of CE patients with a clinical responseof cure (defined as investigator assessment of cure or improvement) inthe daily dose group compared to, 1) the single dose group and 2) theinfrequent dose group. Adjusted estimates for the differences inresponse rates and the corresponding confidence intervals (CI) wereconstructed using the Mantel-Haenszel method stratified by diseasecategory.

The designed study used a sample size that was calculated assuming a2-sided 90% confidence interval for the difference in response rates at85% with a 15% non-inferiority margin at 80% power. Using theseassumptions, a total of 210 clinically evaluable patients (70 per arm)were needed. Assuming an evaluability rate of 70%, 300 total patients(100 per arm) needed to be enrolled to obtain 210 CE patients.

Results

Patients.

A total of 302 patients were randomized and received study medication(100 in the daily dose, 99 in the single dose, and 103 in the infrequentdose groups) with 228 (75.5%) of these patients being clinicallyevaluable (Table 1). Two patients in the ITT population were potentiallyunblinded prior to completing the study. These two patients were notincluded in any efficacy populations, but were included in all safetyanalyses. In the ITT population, 88.9% of patients in the single dosegroup, 86.4% of patients in the infrequent dose group, and 89.0% ofpatients in the daily dose group completed IV therapy. In the ITTpopulation there were 96 patients with wound infections (19 surgical, 47trauma, 1 infected burn and 29 skin ulcers), 114 with major abscesses,and 92 with cellulitis. Demographics and baseline characteristics werecomparable between the three dosing regimens (Table 2).

TABLE 1 Oritavancin Oritavancin Oritavancin 800 mg 200 mg 1200 mg All800 mg 800/400 mg Total N = 100 N = 99 N = 103 N = 34 N = 69 N = 302Patient Population n (%) Intent-to-Treat^(a) 98 (98) 99 (100)  103(100)   34 (100)  69 (100)  300 (99.3) Clinically Evaluable 76 (76) 81(81.8) 71 (68.9) 23 (67.6) 48 (69.6) 228 (75.5) Modified Intent-to-Treat72 (72) 68 (68.7) 69 (67.0) 18 (52.9) 51 (73.9) 209 (69.2)Microbiologically Evaluable 55 (55) 58 (58.6) 48 (46.6) 11 (32.4) 37(53.6) 161 (53.3) ^(a)Two patients in the intent-to-treat populationwere unblinded prior to completing the study. These two patients werenot included in any efficacy populations, but were included in allsafety analyses

TABLE 2 Oritavancin Oritavancin Oritavancin 200 mg 1200 mg 800 mgCharacteristic N = 98 N = 99 N = 103 Male patients 70 (71.4) 64 (64.6)64 (62.1) Age, median (range), years 47.0 (18-87)  46 (18-94)  45(18-86) Weight, mean ± SD, kg 75.6 ± 19.0 77.8 ± 18.1 76.2 ± 18.2 RaceCaucasian 64 (65.3) 65 (65.7) 61 (59.2) Asian 22 (22.4) 22 (22.2) 27(26.2) African descent 5 (5.1) 5 (5.1) 12 (11.7) Other^(a) 7 (7.1) 7(7.1) 3 (2.9) Co-morbid conditions Diabetes 13 (13.3) 15 (15.2) 22(21.4) Impaired renal function 7/97 (7.2)  6/97 (6.2)  4/102 (3.9)  (estimated creatinine clearance ≦50 mL/min)^(b) Disease category Woundinfection 32 (32.7) 30 (30.3) 34 (33.0) Major abscess 36 (36.7) 39(39.4) 38 (36.9) Cellulitis 30 (30.6) 30 (30.3) 31 (30.1) Clinical signFever (>38° C.) 22 (22.4) 27 (27.3) 20 (19.4) White blood cell 45 (45.9)38 (38.4) 49 (47.6) count >10,000/mm³ Deepest tissue involved Skin 4(4.1) 3 (3.0) 6 (5.8) Subcutaneous 82 (83.7) 85 (85.9) 86 (83.5) Muscle1 (1.0) 0 1 (1.0) Fascial Plane 7 (7.1) 5 (5.1) 9 (8.7) Other 4 (4.1) 6(6.1) 1 (1.0) Duration of disease, 2.5 (5.27) 1.9 (1.34) 2.9 (6.38) mean± SD, days Concomitant antibacterial therapy used for primary cSSSIAztreonam 7 (7.1) 3 (3.0) 7 (6.8) Metronizadole 8 (8.2) 3 (3.0) 12(11.7) Note: data are n (%) of patients unless otherwise indicated^(a)Other included mixed-racial parentage, American Indian, Alaskanative, Native Hawaiian or other Pacific Islander ^(b)Estimatedcreatinine clearance was calculated using the Cockcroft-Gault formulaand baseline serum creatinine

Baseline Pathogens and Susceptibility.

At least one gram-positive organism was isolated from the infection siteat baseline in 209 patients (69.2%) in the ITT population. The mostcommonly isolated pathogen was S. aureus, which was isolated from 87.6%(183/209) of MITT patients. MRSA was isolated in 49% (103/209) of MITTpatients. The other three most common pathogens identified in the MITTpopulation were Streptococcus pyogenes (5.7%, 12/209), Streptococcusagalactiae (3.8%, 8/209) and Enterococcus faecalis (3.8%, 8/209). Therange of oritavancin minimum inhibitory concentrations (MICS) for S.aureus in the MITT population, as assessed using broth microdilutionwith 0.002% polysorbate-80, was 0.008 to 0.5 μg/mL. The oritavancinMIC₉₀ for all S. aureus and for the MSSA and MRSA subsets was 0.12μg/mL.

Clinical Efficacy.

Oritavancin single and infrequent doses demonstrated non-inferiority tooritavancin daily dose with clinical cure rates at TOC in the CEpopulation of 72.4% (55/76), 81.5% (66/81), and 77.5% (55/71) in thedaily dose, single dose, and infrequent dose groups, respectively (Table3). The estimated difference in cure rates along with 90% CIs betweenthe single and daily dose groups was 8.6% (−2.5, 18.2) and between theinfrequent and daily dose groups was 5.2% (−6.8, 15.4) demonstratingnon-inferiority of the single and infrequent dose regimens. Clinicallyevaluable patients in the infrequent dose group who only received 800 mgon Day 1 (23/71) and those who received 800 mg on Day 1 plus theoptional 400 mg dose on Day 5 (48/71) had cure rates of 78.3% (18/23)and 77.1% (37/48), respectively, which were comparable to overall curerates. Cure rates by disease category were comparable between alltreatment groups for wound infection and major abscess and between theinfrequent and daily dose of patients with cellulitis (Table 3). Astatistically higher cure rate (90% CI; 9.2, 49.1) was seen for patientswith cellulitis in the single dose group (87.5%) compared to the dailydose group (58.3%). More patients with cellulitis who failed in thedaily dose group had unplanned surgical procedures or interventions(4/14, 29%) than in the single (0/9) or infrequent dose groups (1/14,7%).

TABLE 3 Oritavancin Oritavancin Oritavancin Estimated Estimated 200 mg1200 mg 800 mg Difference^(b) Difference^(b) N = 98^(a) N = 99 N = 1031200 mg − 200 mg 800 mg − 200 mg Response % (n of patients/total) (90%CI) (90% CI) Intent to treat 72.4 (63/87) 81.8 (72/88) 78.2 (68/87) 8.7(−1.7, 17.8)  5.1 (−5.8, 14.6) Cure Clinically evaluable 72.4 (55/76)81.5 (66/81) 77.5 (55/71) 8.6 (−2.5, 18.2)  5.2 (−6.8, 15.4) CureClinically evaluable cure rates by disease category Wound 65.4 (17/26)66.7 (18/27) 72.0 (18/25)  1.3 (−20.1, 22.7)  6.6 (−14.7, 27.9) Major92.3 (24/26) 90.0 (27/30) 87.5 (2124)  −2.3 (−14.8, 10.1) −4.8 (−18.9,9.2) abscess Cellulitis 58.3 (14/24) 87.5 (21/24) 72.7 (16/22) 29.2(9.2, 49.1)^(c )  14.4 (−8.4, 37.2) Modified intent-to-treat 68.8(44/64) 80.3 (49/61) 80.6 (50/62) 10.1 (−2.7, 20.9)  11.1 (−1.5, 21.7)Cure Microbiologically evaluable 69.1 (38/55) 79.3 (46/58) 81.3 (39/48)8.5 (−5.2, 20.0) 11.0 (−2.9, 22.6) Cure Note: Cure includes cure andimprovement outcomes ^(a)Two patients in the intent-to-treat populationwere unblinded prior to completing the study. These two patients aretherefore not included in any efficacy analyses (ITT N = 98), but willbe included in all safety analyses (ITT, N = 100) ^(b)Difference inresponse rate between patients by using Mantel-Haenszel methodstratified by disease ^(c)After data analysis was complete it wasdiscovered that one patient randomized to the single dose group actuallyreceived 6 days of 200 mg/day. A sensitivity analysis was performed byswitching the patient from single dose group to daily dose group and thestatistical significance remained unchanged in the cellulitis diseasecategory.

The cure rates at TOC were 67.4%, 78.9%, and 79.5% for patients with S.aureus at baseline and 78.3%, 73.0%, and 87.0% for patients with MRSA atbaseline in the daily dose, single dose, and infrequent dose groups,respectively (Table 4). There was no obvious relationship betweenoritavancin MIC and rate of cure for patients including those with S.aureus and MRSA at baseline at TOC in the ME population and very fewisolates had a MIC above 0.12 (FIGS. 1 and 2).

TABLE 4 Oritavancin Oritavancin Oritavancin 200 mg 1200 mg 800 mg % ofpatients cured Pathogen (n of patients/total) Staphylococcus aureus 67.4(31/46) 78.9 (45/57) 79.5 (31/39) MRSA 78.3 (18/23) 73.0 (27/37) 87.0(20/23) MSSA 56.5 (13/23) 90.9 (20/22) 68.8 (11/16) Streptococcuspyogenes 66.7 (4/6)  100 (1/1)  100 (2/2) Streptococcus agalactiae 33.3(1/3)  100 (1/1)  100 (1/1) Enterococcus faecalis 50.0 (2/4)  100 (1/1) 100 (3/3) Note: Cure includes cure and improvement outcomes

Relapse rates in CE patients were low with no patients in the daily dosegroup, 1/61 (1.6%) patients in the single, and 2/54 (3.7%) patients inthe infrequent dose groups experiencing relapse. In the ITT populationthe mean duration of study medication (oritavancin or placebo) wassimilar in the daily, single, and infrequent dose groups, (5.4, 5.1, and5.2 days, respectively).

Safety and Tolerability.

Overall, safety findings were comparable between the three treatmentgroups. The most common reason for early discontinuation of studymedication was lack of efficacy (3.3%, 10/302). The most common adverseevents were nausea, phlebitis, diarrhea, headache, infusion siteextravasation, vomiting, and constipation. There was a higher incidenceof blood creatine phosphokinase (CPK) increase in the single dose groupcompared to the daily and infrequent dose groups. Review of these casesshowed that patients with increases in CPK had mild, asymptomaticelevations from normal or were already slightly elevated at baseline.Most had normalized by last visit. In one subject the elevation was onlyobserved at day 35.

The majority of adverse events were considered by the investigator to bemild or moderate in intensity (85.7%, 94.5%, and 95.2% in the daily,single, and infrequent dose groups, respectively) with more than half ineach treatment group being mild (51.8%, 58.2%, and 60.3%). The majorityof adverse events were unrelated to study medication. Of the adverseevents that the investigator recorded as related to study medication,phlebitis, diarrhea, and nausea were the most common The percentage ofpatients with phlebitis that was assessed by the investigator as beingrelated to study medication was 3.0% (3/100), 4.0% (4/99), and 8.7%(9/103) in the daily, single, and infrequent dose groups, respectivelyand none of the phlebitis events were severe. In the infrequent dosegroup the percentage of patients with related phlebitis was 11.8% (4/34)in patients who received 800 mg only and 7.2% (5/69) in patients whoreceived 800 mg plus the 400 mg dose.

A total of 25 patients (8.3%) had a serious adverse event. The incidenceof serious adverse events was higher in the daily dose group (11%,11/100) compared to the single dose group (7.1%, 7/99), and theinfrequent dose group (6.8%, 7/103). Two patients in the single dosegroup had a serious adverse event that was investigator-assessed asbeing related to study medication. One patient suffered dyspnoea and theother patient suffered hypersensitivity. Five patients died during thestudy (3/100 in the daily dose group, 0/99 in the single dose group, and2/103 in the infrequent dose group). The adverse events leading to thedeaths were cardiac arrest, cardiopulmonary failure, septic shock,myocardial infarction, and pulmonary embolism. None of the deaths wereinvestigator-assessed as being related to study medication and nopatients died during therapy. A total of seven patients discontinuedstudy medication due to an adverse event (3.0% [3/100], 3.0% [3/99], and1.0% [1/103] in the daily, single, and infrequent dose groups,respectively). The adverse events leading to early discontinuation ofstudy medication were abscess, gangrene, catheter site pain, renalimpairment, eye pruritis, and hypersensitivity (2 patients).

Vital signs data were unremarkable and typical of patients being treatedfor complicated skin and skin structure infections. There were noclinically significant treatment group differences in these parametersor any indication of unexpected adverse systemic effects of thetreatment.

The evidence provided by this study demonstrates that oritavancin givenas a single dose of 1200 mg or an infrequent dose of 800 mg with anoptional 400 mg on Day 5 is non-inferior to a 200 mg daily dose for 3 to7 days in treatment of patients with complicated skin and skin structureinfections. This study provides evidence for the effectiveness of singledose or infrequent dosing of oritavancin in the treatment of cSSSI.Single and infrequent doses of oritavancin were as efficacious as dailydoses for complicated skin and skin structure infections caused bygram-positive pathogens, including MRSA. Safety and tolerability weresimilar among dosing groups.

Example 2 Comparative Efficacy of Oritavancin (ORI) AgainstMethicillin-Sensitive and -Resistant Staphylococcus aureus Strains in aNeutropenic-Mouse Thigh Infection Model

Oritavancin (ORI) is a novel lipoglycopeptide with a highly potent invitro activity against most gram-positive bacteria includingpenicillin-resistant Streptococcus pneumoniae, methicillin-resistantStaphylococcus aureus (MRSA) and vancomycin (VAN)-resistant Enterococci(VRE) (Allen, N. E. and T. I. Nicas, FEMS Microbiol Rev 26(5): 511-32(2003); Arhin et al., Antimicrob Agents Chemother 52(5): 1597-603(2008)).

In this study, single bolus and human equivalent (HEQ) doses ofOritavancin (ORI) were used to compare its activity against MSSA andMRSA clinical isolates in a murine thigh-infection model.

Methods: Thigh infection was established for 14 clinical SA isolates (3MSSA and 11 MRSA; MICs 0.0015 to 2 μg/mL) in neutropenic CD-1 mice(n=3/group) with 5×10⁵ colony forming units (CFU) of cells. Singleintravenous doses of ORI (0.5 to 40 mg/kg) were tested against one MSSAand one MRSA strain. Efficacy of ORI doses simulating human exposure(HEQ doses, i.e. 24 h AUC-matched) of 100 or 200 or 400 mg daily×3 days,and a single 1200 mg HEQ dose were also evaluated against the MSSA andMRSA strains. Both thighs were harvested and CFU counts were evaluatedafter 24 h (single doses) or 72 h (HEQ doses) treatment.

Strains: Fourteen clinical S. aureus isolates (3 MSSA and 11 MRSA; MICs0.0015 to 2 μg/mL) were used in this study. MICs were determined by thebroth microdilution assay against oritavancin following CLSI guidelinesand included polysorbate-80 (final test concentration of 0.002%) asdescribed previously (Arhin et al., Antimicrob Agents Chemother 52(5):1597-603 (2008)).

In vivo studies: All studies were performed in accordance with protocolsthat were approved by the Institutional Animal Care and Use Committee.Thigh infection was established for 14 clinical S. aureus isolates inneutropenic CD-1 mice (19-21 g, n=3/group) with 5×10⁵ colony formingunits (CFU) of cells in both thighs. In the single dose-response study,the number of bacteria/thigh was monitored 24 h post-infection (PI). Inthe human equivalent (HEQ) dose-ranging study, the bacterial titer wasdetermined in mouse thighs at 2, 4, 8, 12, 24, 48 and 72 h PI. Thighswere serially diluted and plated on Baird-Parker agar plates todetermine the bacterial titer. The limit of detection was 1.69 Log₁₀CFU/thigh. Bacterial titer decreases were calculated (compared tostarting inoculum) in thighs at 72 h PI for each HEQ dose regimen ofORI.

Antibiotherapy: 1) In the single dose response study, mice were treatedintravenously (IV) with ORI at doses ranging from 0.4 to 40 mg/kg at 1 hPI. 2) In the HEQ dose-ranging study, starting at 1 h PI, the micereceived a multiple IV dose regimen to simulate human drug concentrationprofile. The following HEQ doses were simulated: daily doses (QD) of100, 400, 800 mg for 72 h, or a single 1200 mg dose (Lehoux et al.“Efficacy of Oritavancin (ORI) in the Mouse Bacteremia Model.” 48thInterscience Conference on Antimicrobial Agents and Chemotherapy; 2008Sep. 25-28; Washington (DC) Poster B-1009).

Data analysis: The inhibitory sigmoid E_(max) model was used tocalculate the ED₅₀ of oritavancin (dose resulting in 50% of the maximalbacterial killing)±95% confidence interval by using the GraphPad Prismsoftware. The statistical calculations to compare bacterial titer fromeach experimental group were performed according to the Mann-Whitney Utest by using StatsDirect software. p-values below 0.05 were consideredsignificant.

Results: The single dose dose-response studies of ORI yielded similarED₅₀ (dose resulting in 50% of the maximal killing): 5.8 mg/kg (95% CI:3.3-10) for MSSA and 2.4 mg/kg (95% CI: 0.8-7.3) for MRSA (FIG. 3).Also, efficacy of ORI was HEQ dose-dependent (FIG. 4). ORI was similarlyefficacious against MSSA and MRSA strains (FIG. 5). Bacterial loadreduction was significantly higher for the single 1200 mg dose comparedto the 200 mg daily dose (p≦0.0005) (Table 5).

TABLE 5 Mean Log CFU/thigh from baseline MSSA MRSA HEQ Dose mean 95% Clmean 95% Cl 100 mg ×  1.5 (n = 3)  0.7 to 2.3  0.8 (n = 3) −0.2 to 1.8 3days 200 mg × −0.1 (n = 3) −1.3 to 1.1 −0.9 (n = 11) −1.9 to −0.2 3 days400 mg × −1.6 (n = 3) −2.7 to −0.6 −2.8 (n = 3) −3.7 to −2.0 3 days 1200mg × −2.7 (n = 3) −3.6 to −1.8 −2.8 (n = 11) −3.3 to −2.3 1 day n =number of strains tested

Conclusions: ORI was equivalently efficacious against MSSA and MRSA invivo. The single dose-response study (1200 mg) revealed that ORI isequivalently efficacious (similar EDO against MSSA and MRSA in the thighmodel.

Example 3

A pharmacokinetic (PK) analysis was conducted of oritavancin frompatients having complicated skin and skin structure infections (cSSSI)or bacteremia. The population for the analysis consisted oforitavancin-treated subjects and patients from 12 studies, consisting ofnine Phase 1 studies, two Phase 2 studies, and one Phase 2/3 study.Oritavancin was administered as both single- and multiple-doseintravenous (IV) infusions in fixed doses ranging from 100 to 800 mg orweight-based doses ranging from 0.02 to 10 mg/kg.

Results: The final analysis population contained data from a total of560 subjects: 200 from the Phase 1 studies, 86 from the Phase 2bacteremia study, 29 from the Phase 2 cSSSI study, and 245 from thePhase 2/3 cSSSI study. The final pharmacokinetic analysis datasetcontained a total of 6,336 oritavancin plasma concentrations, collectedfrom these 560 subjects, of which 6,290 oritavancin concentrations wereincluded in the results. The majority of subjects (>90%) contributed atleast six samples to the population pharmacokinetic analysis.

A wide range of oritavancin doses was administered across the studiesincluded in the population PK analysis, where 42% (236 of 560) ofsubjects received ≧400 mg, while 25% (142 of 560) received 800 mg ormore. A histogram of the oritavancin doses administered is shown in FIG.6, with midpoint values for each dose range shown over each bar. Theduration over which oritavancin was infused ranged from 0.13 to 6.5 hracross all studies; however, oritavancin was administered over 1 hr forthe majority of subjects. Histograms of the actual infusion durationsand rates are shown in FIGS. 7 and 8, respectively, with midpoint valuesshown for each infusion duration or rate over each bar.

The range of doses allowed for a robust assessment of thedose-proportionality (also termed linearity) of the PK of oritavancin.Although a formal statistical assessment of dose-proportionality was notperformed, the goodness-of-fit of the final population PK model was usedto detect any apparent lack of dose-proportionality.

The final structural PK model for oritavancin in this analysis was athree-compartment model (one central, two peripheral) with a zero-orderintravenous infusion rate and first-order, linear elimination. The modelfit the data well (data not shown), regardless of the observedconcentration or administered dose. If a nonlinear model had beennecessary, there would have been significant bias in the weightedresiduals at the lowest and/or highest concentrations and/or doses. Notrends for decreasing CL with increasing dose were found. The summarystatistics of key PK parameter estimates, stratified by dose, areprovided in Table 6.

TABLE 6 <180 mg/day 180-330 mg/day >330 mg/day (n = 181) (n = 140) (n =239) Mean Median Mean Median Mean Median Variable (SD) (Min-Max) (SD)(Min-Max) (SD) (Min-Max) Dose (mg)  114 (37.9) 113 (1.00-179)  239(40.4) 231 (180-330)  682 (179)  800 (333-1220) CL (L/hr) 0.558 (0.194)0.550 (0.169-1.40) 0.574 (0.219) 0.544 (0.208-1.45) 0.441 (0.202) 0.401(0.121-1.43) T_(1/2, α) (hr)  2.01 (0.467)  1.97 (0.939-3.55)  2.13(0.460)  2.13 (0.910-3.27)  2.45 (0.643) 2.35 (1.03-4.78) T_(1/2, β)(hr) 27.4 (7.89) 27.5 (8.37-58.3) 29.7 (9.97) 29.3 (10.4-81.5) 31.4(14.2) 29.3 (9.38-99.6) T_(1/2, γ) (hr)  376 (71.1) 387 (142-567)   376(77.5) 373 (192-545)   353 (80.8) 347 (166-302)  AUC₀₋₂₄ (μg*h/mL) 90.0(61.7) 73.6 (1.02-519)   181 (77.1) 171 (46.5-424) 750 (412)  712(109-2090) Cmax (μg/mL) 17.8 (11.5)  14.3 (0.156-87.2) 33.4 (13.2) 30.0(12.4-92.7)  106 (42.2) 105 (20.4-251) Cmin (μg/mL)  1.17 (0.813) 0.949(0.016-6.78) 2.58 (1.45)  2.20 (0.452-8.00) 12.5 (8.74) 11.0 (1.41-40.7)

A semilog scatterplot of oritavancin concentrations versus time sincestart of last infusion, stratified by dose range, following a singledose of oritavancin is shown in FIG. 9. The summary statistics of key PKparameter estimates for healthy subjects are provided in Table 7.

TABLE 7 Single Dose Multiple Dose Variable (n = 91) (n = 109) CL 0.402(26.0) 0.309 (30.2) (L/hr) Vc 5.30 (20.0) 5.10 (28.1) (L) T_(1/2,α) 2.25(24.4) 2.82 (22.0) (hr) T_(1/2,β) 19.8 (28.2) 33.0 (35.3) (hr) T_(1/2,γ)316 (16.9) 320 (19.9) (hr) AUC₀₋₂₄ 216 (28.6) 459 (160)^(b) (μg *h/mL)^(a) Cmax 33.9 (22.5) 46.8 (14.0)^(b) (μg/mL)^(a) Cmin 3.30 (41.8)11.5 (4.71)^(b) (μg/mL)^(a) ^(a)AUC₀₋₂₄, Cmax, and Cmin have beennormalized to a dose of 200 mg to ease comparisons across groups.^(b)Exposure parameters obtained after a median (min-max) of 4 (2-14)days.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims.

All documents, including but not limited to publications, patents,patent applications, books, manuals, articles, papers, abstracts, andposters, and other materials referenced herein are expresslyincorporated herein by reference in their entireties.

We claim:
 1. A method of treating a bacterial infection in a subject,comprising administering one dose of a therapeutically effective amountof a pharmaceutical composition comprising oritavancin, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or diluent, over a course of therapy to a subjecthaving a bacterial infection, thereby treating a bacterial infection ina subject.
 2. The method of claim 1, wherein the one dose comprises atleast about 400 mg oritavancin, or a pharmaceutically acceptable saltthereof.
 3. The method of claim 1, wherein the one dose comprisesbetween about 400 mg to about 1800 mg oritavancin, or a pharmaceuticallyacceptable salt thereof.
 4. The method of claim 1, wherein the one dosecomprises about 800 mg oritavancin, or a pharmaceutically acceptablesalt thereof.
 5. The method of claim 1, wherein the one dose comprisesabout 900 mg oritavancin, or a pharmaceutically acceptable salt thereof.6. The method of claim 1, further comprising administering a second doseof a therapeutically effective amount of a pharmaceutical compositioncomprising oritavancin, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier or diluent, within the courseof therapy.
 7. The method of claim 6, wherein the second dose comprisesan amount of oritavancin less than or equal to that of the first dose.8. The method of claim 6, wherein the second dose is administered about4 days or more after the first dose.
 9. The method of claim 1, whereinsaid administering is via intravenous administration or oraladministration.
 10. The method of claim 1, wherein the infectiousbacteria and the bacteria causing a bacterial infection is a bacteriaselected from the group consisting of a gram-positive bacteria,Staphylococcus aureus, methicillin-resistant Staphylococcus aureus,vancomycin-resistant Staphylococcus aureus, vancomycin-intermediateStaphylococcus aureus, vancomycin hetero-intermediate Staphylococcusaureus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcusanginosus, Streptococcus intermedius, Streptococcus constellatus,Streptococcus dysgalactiae, Streptococcus dysgalactiae subsp.equisimilis, Streptococcus pneumoniae, Group A Streptococci species,Group B Streptococci species, Group C Streptococci species, Group DStreptococci species, Enterococci species, Enterococcus faecalis,vancomycin-resistant Enterococcus faecalis, Enterococcus faecium,vancomycin-resistant Enterococcus faecium, Staphylococcus epidermidis,methicillin-resistant Staphylococcus epidermidis, Staphylococcushaemolyticus, Bacillus anthracis and Clostridium difficile.
 11. A methodof treating a bacterial infection in a subject, comprising administeringone dose of a pharmaceutical composition comprising oritavancin, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or diluent, over a course of therapy to a subjecthaving a bacterial infection, in an amount sufficient to achieve amaximum plasma concentration (C_(max)) of oritavancin of not less thanabout 20 μg/mL.
 12. The method of claim 11, wherein the C_(max) oforitavancin is not less than about 40 μg/mL.
 13. The method of claim 11,further comprising administering a second dose of a therapeuticallyeffective amount of a pharmaceutical composition comprising oritavancin,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or diluent, within the course of therapy.
 14. Themethod of claim 13, wherein the second dose comprises an amount oforitavancin less than or equal to that of the first dose.
 15. The methodof claim 13, wherein the second dose is administered about 4 days ormore after the first dose.
 16. A method of treating a bacterialinfection in a subject, comprising administering one dose of apharmaceutical composition comprising oritavancin, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier ordiluent, over a course of therapy to a subject having a bacterialinfection, in an amount sufficient to achieve an area under theconcentration curve (AUC 0-24 hr) of oritavancin of at least about 20μg*h/mL.
 17. The method of claim 16, wherein the AUC 0-24 hr oforitavancin is at least about 40 μg*h/mL.
 18. The method of claim 16,further comprising administering a second dose of a therapeuticallyeffective amount of a pharmaceutical composition comprising oritavancin,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or diluent, within the course of therapy.
 19. Themethod of claim 18, wherein the second dose comprises an amount oforitavancin less than or equal to that of the first dose.
 20. The methodof claim 18, wherein the second dose is administered about 4 days ormore after the first dose.